Lung cancer is a cancer having the highest incidence in the world. In China, the incidence of lung cancer ranks first among all cancers, and the incidence and mortality rate of the lung cancer are also the highest in all diseases in China. In the lung cancer patients in China, 30% of patients have EGFR mutations, over 90% of which are L858R and exon 19 deletion mutation, and these patients are more sensitive to EGFR inhibitors. The marketed first-generation of EGFR inhibitors, such as erlotinib, gefitinib have good effects in these patients, and the tumors in more than 60% of patients will shrink, thereby significantly prolonging the progression-free survival of patients. However, most of patients acquire resistance in 6-12 months so that the first generation of EGFR inhibitors will be no longer effective, and currently no drugs are available for these patients. EGFR T790M mutation is clinically detected in 50% of patients who are resistant to the first-generation of EGFR inhibitors. In T790M mutant cell line H1975, the first-generation of EGFR inhibitors, such as gefitinib and erlotinib, are more than 3 uM, which means almost no activity.
The therapeutic effect of the second generation of irreversible pan-EGFR inhibitors (Afatinib (BIBW2992)) which are currently launched is significantly better than that of the first-generation of EGFR inhibitors in lung cancer patients with EGFR mutations. However, the second-generation of inhibitors also have strong inhibitory activity on wild-type EGFR, and the inhibitory activity on wild-type EGFR are significantly higher than that on resistant T790M mutation. Side effects, such as skin rashes, are severe in some patients. The effect of the second-generation of inhibitors in drug resistant patients is poor, and only a small portion of patients resistant to the first generation of EGFR inhibitors response to these drugs.
In order to improve the inhibitory activity on resistant T790M mutation and reduce the inhibitory activity on wild-type EGFR, it is greatly significant to develop the third generation of selective inhibitors for EGFR mutants with higher activity, better selectivity, and lower toxicity.